Pharmacokinetics:
Absorption/Distribution: Carvedilol is rapidly and extensively absorbed following oral administration, which absolute bioavailability of 25 to 35 %
Due to a significant degree of first-pass metabolism. Following oral administration, the apparent mean terminal elimination half-life generally ranges from 7 to 10 hours. Plasma concentrations achieved are proportional to the oral dose administered.

Metabolism/Excretion: Carvedilol is extensively metabolized.
Less than 2% of the dose was excreted unchanged in the urine. The metabolites of Carvedilol are excreted primarily via the bile into the feces.

Indications:

Congestive Heart Failure:
Carvilol is indicated for the treatment of mild or
Moderate (NYHA class II or III) heart failure of ischemic or car-diomyopathic
Origin, in conjunction with digitalis, diuretics, and ACE inhibitor, to reduce the progression of disease as evidenced by cardiovascular death, cardiovascular hospitalization, or the need to adjust other heart failure medication.
Carvilol may be used in patients unable to tolerate an ACE inhibitor. Carvilol may be used in patients who are or are not receiving digitalis, hydralazine or nitrate therapy.

Hypertension: Carvilol (Carvedilol) is also indicated for the management of essential hypertension. It can be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics.

Contraindications:

Carvilol is contraindicated in patients with NYHA class IV decompensated cardiac failure requiring intravenous inotropic therapy, bronchial asthma or related bronchospastic conditions, second - or third - degree AV block, sick sinus syndrome (unless a permanent pacemaker is in place), cardiogenic shock or severe bradycardia.
Use of Carvilol in patients with clinically manifest hepatic impairment is not recommended.
Carvilol is contraindicated in patients with hypersensitivity to the drug.

Use with caution in patients with cobgestive heart failure treated with digitalis, diuretics, or ACE inhibitor since A-V

conduction may be slowed:
discontinue therapy if any evidence of liver injury occurs; use caution in patients with peripheral vascular disease, those undergoing anesthesia, in hyperthyroidism and diabetes mellitus.

If no other antihypertensive is tolerated, very small doses may be cautiously used inpatients with bronchospastic disease. Abrupt with drawal of the drug should be avoided, drug should be discontinued over 1-2 weeks:

do not use in pregnant or nursing woman; may poteniate hypoglycemia in a diabetic patient and mask signs and symptoms; safety and efficacy in children have not been established.

Drug Interactions:

Decreased effect: Rifampin may reduce the plasma concentration of carvedilol by up to 70%; decreased effect has also occurred with aluminum salts, barbiturates, calcium salts, cholestyramine, colestipol, NSAIDs, penicillins (ampicillin), salicylates, and sulfinpyrazone due to decreased bioavailability and plasma levels; beta-blockers may decrease the effect of sulfonylureas.

Increased effects: Carvedilol may enhance the action of antidiabetic agents, calcium channel blockers, digoxin; clonidine and carvedilol may result in augmented blood pressure and heart rate lowering effects. Other drugs likely to increase carvedilol’s levels and effects include quinidine, fluoxetine, paroxetine, and propafenone since these drugs inhibit CYP2D6.
Increased effect/toxicity of other beta-blockers occurs with contraceptives flecainide, epinephrine (initial hypertensive episode followed by bradycardia), lidocaine, ergots (peripheral), and prazosin(postural hypotension).

Dosage:

Congestive Heart Failure: dosage must be individualized and closely monitored by a physician during up-titration. Prior to initiation of Carvilol ,

the dosing of digitalis, diuretics and ACE inhibitors (if used) should be stabilized. The recommended starting dose of Carvilol is 3.125 mg twice daily for two weeks. If this dose is tolerated, it can then be increased to 6.25 mg twice daily. Dosing should then be doubled every 2 weeks to the highest level tolerated by the patient. At initiation of each new dose,

patients should be observed for signs of dizziness or light-headedness for one hour. The maximum recommended dose is 25 mg twice daily in patients weighimg less than 85 kg and 50 mg twice daily in patients weighing more than 85kg.

Carvilol should be taken with food to slow the raate of absorption and reduce the incidence of orthostatic effects.

Before each dose increase the patient should be seen in the office and evaluated for symptoms of worsening heart failure, vasodilation (dizziness, light-headedness, symptomatic hypotension) or bradycardia, in order to
determine tolerability of Carvilol. Transient worsening of heart failure may be treated with increased doses of diuretics although occasionally it is necessary to lower the dose of Carvilol or temporarily discontinue it. Symptoms of vasodilation often respond to a reduction in the dose of diuretics or ACE inhibitor. If these changes do not relieve symptoms, the dose of Carvilol may be decreased. The dose of Carvilol should not be increased until symptoms of worsening heart failure or vasodilation have been stabilized. Initial difficulty with titration should not preclude later attempts to introduce Carvilol.

Hypertension: Dosage must be individualized. The recommended starting dose Carvilol is6.25 mg twice daily. if this dose is tolerated, using standing systolic pressure measured about 1 hour after dosing as a guide, the dose should be maintained for 7 to 14 days, and then increased to 12.5 mg twice daily if needed, based on trough blood pressure, again using standing systolic pressure one hour after dosing as a guide for tolerance. This dose should also be maintained for 7 to 14 days and can then be adjusted upward to 25mg twice daily

if tolerated and needed. The full antihypertensive effect of Carvilol is seen within 7 to 14 days. Total daily dose should not exceed 50 mg. Carvilol should be taken with food to slow the rate of absorption and reduce the incidence of orthostatic.

Addition of a diuretic to Carvilol, or Carvilol to a diuretic can be expected to produce additive effects and exaggerate the orthostatic component of Carvilol action .
Carvilol (Carvedilol) should not be given to patients with server hepatic impairment.

The patient should be placed in a supine position and, where necessary, kept under observation and treated under intensive-care conditions. Gastric lavage or pharmacologically induced emesis may be used shortly after ingestion.